Consumer medicine information

Telzir Tablets

Fosamprenavir

BRAND INFORMATION

Brand name

Telzir

Active ingredient

Fosamprenavir

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Telzir Tablets.

SUMMARY CMI

TELZIR

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking TELZIR?

TELZIR contains the active ingredient fosamprenavir which belongs to a group of antiretroviral medicines called protease inhibitors. TELZIR is taken with ritonavir and is used to slow down the progression of human immunodeficiency virus (HIV) infection which can lead to Acquired Immune Deficiency Syndrome (AIDS) and other related illnesses (e.g. AIDS-related Complex (ARC)).

For more information, see Section 1. Why am I taking TELZIR? in the full CMI.

2. What should I know before I use TELZIR?

Do not use if you have ever had an allergic or hypersensitivity reaction to fosamprenavir, amprenavir, ritonavir or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take TELZIR? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TELZIR and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take TELZIR?

  • Adults over the age of 18 in treatment-naïve patients: the dose is 1400 mg (two tablets) once a day with 200 mg ritonavir once a day or 700 mg (one tablet) twice a day with 100 mg ritonavir twice a day.
  • Adults over the age of 18 in protease inhibitor experienced patients: the dose is 700 mg (one tablet) with 100 mg ritonavir twice a day in combination with other antiretroviral agents.
  • In children and adolescents between 6 and 18: 700 mg (one tablet) twice a day plus 100 mg ritonavir twice a day.

More instructions can be found in Section 4. How do I take TELZIR? in the full CMI.

5. What should I know while using TELZIR?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking TELZIR.
  • Have blood tests when you are meant to so your doctor can check for side effects.
  • Keep in contact with your doctor and don't stop taking TELZIR without talking to your doctor.
Things you should not do
  • Do not stop using this medicine suddenly or change the dose without talking to your doctor.
  • Do not take this medicine to treat any other complaints.
Driving or using machines
  • TELZIR can make you dizzy and have other side effects that make you less alert.
  • Do not drive or use a machine unless you are sure you are not affected.
Looking after your medicine
  • Store TELZIR below 30°C in the pack.
  • Keep your tablets in the bottle until it is time to take them.

For more information, see Section 5. What should I know while using TELZIR? in the full CMI.

6. Are there any side effects?

Side effects that have been reported include: nausea, vomiting, diarrhoea, flatulence, abdominal pain, headache, rash, fatigue, feeling tired, an altered sensation in your mouth, dizziness, muscle pain, tenderness and weakness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

TELZIR

Active ingredient(s): fosamprenavir

Consumer Medicine Information (CMI)

This leaflet provides important information about using TELZIR. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TELZIR.

Where to find information in this leaflet:

1. Why am I taking TELZIR?
2. What should I know before I take TELZIR?
3. What if I am taking other medicines?
4. How do I take TELZIR?
5. What should I know while taking TELZIR?
6. Are there any side effects?
7. Product details

1. Why am I taking TELZIR?

TELZIR contains the active ingredient fosamprenavir. TELZIR belongs to a group of antiretroviral medicines called protease inhibitors.

TELZIR is taken with another HIV medicine called ritonavir and is used to slow down the progression of human immunodeficiency virus (HIV) infection which can lead to Acquired Immune Deficiency Syndrome (AIDS) and other related illnesses (e.g. AIDS-related Complex (ARC)).

The low doses of ritonavir you take together with TELZIR are designed to increase the amount of the active ingredient, amprenavir, available to control your HIV infection.

TELZIR does not cure AIDS or HIV infection however it slows down production of HIV in the body. In this way it stops ongoing damage to the body's immune system which fights infection.

You can still pass on HIV when taking this medicine through sexual activity or through passing on blood or bodily secretions which carry the HIV virus, although the risk is lowered by taking antiretroviral therapy.

You should use proper precautions to prevent this from occurring. Discuss with your doctor the precautions needed to avoid infecting other people.

While taking TELZIR and/or any other therapy for HIV, you may continue to develop other infections and other complications of HIV infection. You should keep in regular contact with your doctor.

It is important to read the patient information relating to ritonavir before you start taking this medicine. Ask your doctor or pharmacist for a copy.

2. What should I know before I take TELZIR?

Warnings

Do not use TELZIR if:

  • you are allergic or had a hypersensitivity reaction to fosamprenavir, amprenavir, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

  • you are allergic to ritonavir or any of the ingredients in that medicine
  • you are pregnant, trying to become pregnant or are breastfeeding
  • you are taking any of the following medicines: astemizole, terfenadine, rifampicin, telaprevir, boceprevir, simeprevir, paritaprevir, midazolam, triazolam, sildenafil, dihydroergotamine, ergotamine, cisapride, pimozide, quetiapine, lurasidone, flecainide, propafenone, St John's Wort

Check with your doctor if you:

  • have any other medical conditions
  • are allergic to food, dyes, preservatives or any other medicines (eg sulfonamide)
  • have diabetes mellitus or haemophilia
  • have or have ever had any liver problems, for example jaundice, hepatitis, a virus affecting your liver, an enlarged liver or liver scarring (cirrhosis)

If you have liver disease you will need to have your dose of TELZIR and/or ritonavir adjusted. It is not possible to reduce the dose of TELZIR tablets to less than 700 mg, so people with moderate or severe liver disease must not be treated with TELZIR tablets. If you are unsure about your level of liver disease consult your doctor who may carry out additional testing to see whether the TELZIR/ritonavir combination is suitable for you.

  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Talk to your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss with you the risks and benefits involved of using TELZIR with ritonavir whilst pregnant or breastfeeding.

If you are taking the contraceptive pill, it is recommended that you use an alternative method of contraception (e.g. a condom) to prevent pregnancy while you are taking TELZIR.

Symptoms of infection and inflammation

People with advanced HIV infection (AIDS) have weak immune systems and are more likely to develop serious infections (opportunistic infections). When they start treatment, the immune system becomes stronger and so the body starts to fight infections.

Symptoms of infection and inflammation may develop, caused by either:

  • old, hidden infections flaring up at the body fights them
  • the immune system attacking healthy body tissue (autoimmune disorders)

The symptoms of autoimmune disorders may develop many months after you start taking medications to treat your HIV infection.

Symptoms may include:

  • muscle weakness and/or muscle pain
  • joint pain or swelling
  • weakness beginning in the hands or feet and moving towards the trunk of the body
  • palpitations or tremor
  • hyperactivity (excessive restlessness and movement)

If you get symptoms of infection or if you notice any of the symptoms above, tell your doctor immediately. Do not take other medicines for the infection without your doctor's advice.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

The following medicines can interact with TELZIR and ritonavir and must not be taken with TELZIR and ritonavir:

  • astemizole and terfenadine, which are used to treat hayfever
  • rifampicin, used to treat tuberculosis
  • telaprevir, boceprevir, simeprevir, paritaprevir and similar medicines used to treat hepatitis C
  • nevirapine, a medicine used to treat HIV
  • midazolam and triazolam, medicines which induce sedation
  • sildenafil when it is used to treat increased pressure in the blood vessels to your lungs
  • dihydroergotamine and ergotamine which are used to treat migraine
  • cisapride which is used to treat gastric reflux
  • pimozide which is used to treat chronic psychotic disorders
  • alfuzosin, a medicine used in men to treat benign prostatic hyperplasia
  • quetiapine, a medicine used to treat schizophrenia, bipolar disorder and major depressive disorder
  • lurasidone, a medicine used to treat schizophrenia and bipolar disorder
  • flecainide which is used to treat heart conditions
  • propafenone which is used to treat heart conditions
  • herbal treatments such as St Johns Wort

TELZIR and ritonavir may interact with certain other medications. The use of these medicines, together with the TELZIR/ritonavir combination, should only take place on the basis of medical advice which may include monitoring decreased medicine effects, monitoring your blood and decreasing dosages:

  • antibiotics such as rifabutin, clarithromycin, dapsone and erythromycin
  • antifungals including ketoconazole, itraconazole
  • halofantrine, an antimalarial medicine
  • benzodiazepines such as alprazolam and clorazepam
  • calcium channel blockers such as diltiazem, nicardipine, nifedipine, nimodipine, felodipine, verapamil, amlodipine, and isradipine
  • medicines used to lower your cholesterol including atorvastatin, lovastatin and simvastatin
  • erectile dysfunction medicines including sildenafil, tadalafil, vardenafil
  • non-nucleoside reverse transcriptase inhibitors such as efavirenz, nevirapine and delavirdine
  • opioids, for example methadone
  • steroids such as oestrogens, progestogens and some glucocorticoids
  • inhaled/nasal steroid including fluticasone
  • immunosuppressants and medicines used to suppress your immune system such as ciclosporin, tacrolimus
  • clozapine, an antipsychotic medicine
  • carbamazepine, a medicine used to in seizures
  • famotidine, nizatidine, ranitidine, cimetidine, medicines used to decrease stomach acid production
  • paroxetine, a medicine used to treat depression
  • loratadine, a medicine used to treat hayfever
  • maraviroc and dolutegravir, medicines used to treat HIV
  • medications used to treat several types of cancers such as dasatinib, nilotinib, ibrutinib, vinblastine and everolimus

If you are taking certain medicines that can cause serious side effects, such as amiodarone, phenobarbitone, phenytoin, lidocaine, tricyclic antidepressants, quinidine and warfarin, at the same time as you are taking the TELZIR/ritonavir combination, your doctor may carry out additional blood tests to minimise any potential safety problems.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TELZIR.

4. How do I take TELZIR?

How much to take

Adults over the age of 18:

  • Treatment-naïve patients: the dose of TELZIR is 1400 mg (two tablets) once a day with 200 mg ritonavir once a day or 700 mg (one tablet) twice a day with 100 mg ritonavir twice a day
  • Protease inhibitor experienced patients: the recommended dose is 700 mg (one tablet) with 100 mg ritonavir twice a day in combination with other antiretroviral agents. The once daily administration of TELZIR plus ritonavir is not recommended in protease inhibitor experienced patients.

Children and adolescents between 6 and 18 years of age:

  • If the child weighs over 39 kg and can swallow the tablets whole then the adult dosing regimen of 700 mg (one tablet) twice a day plus 100 mg ritonavir twice a day can be used. Ritonavir 100 mg capsules can be used by children and adolescents who weigh more than 33 kg and can swallow the capsules whole.

The use of TELZIR in combination with ritonavir has not been established in children less than 6 years of age.

Follow the instructions provided and use TELZIR until your doctor tells you to stop.

How to take TELZIR

  • Swallow the tablets whole with a glass of water.
  • You can take TELZIR with or without food.

If you forget to take TELZIR

TELZIR should be used regularly at the same time each day.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you take too much TELZIR

If you think that you have used too much TELZIR, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking TELZIR?

Things you should do

Tell your doctor straight away if you:

  • become pregnant or intend to become pregnant
  • have not taken TELZIR as intended

Remind any doctor, dentist or pharmacist you visit that you are taking TELZIR.

Stay in regular contact with your doctor

TELZIR helps to control your condition, but it is not a cure for HIV infection. You need to keep taking it every day to stop your illness from getting worse. Because TELZIR does not cure HIV infections, you may still develop other infections and illnesses linked to HIV.

Things you should not do

  • Do not stop taking this medicine suddenly or change the dose.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use this medicine to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TELZIR affects you.

Looking after your medicine

Follow the instructions on the pack on how to take care of your medicine properly.

Store it in a cool dry place (below 30°C) away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Within the first few weeks of treatment with anti-HIV medicines, some people, particularly those that have been HIV positive for some time, may develop inflammatory reactions (e.g. pain, redness, swelling, high temperature) which may resemble an infection and may be severe. It is thought that these reactions are caused by a recovery in the body's ability to fight infections, previously suppressed by HIV.

If you become concerned about any new symptoms, or any changes in your health after starting HIV treatment, discuss with your doctor immediately.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal
  • nausea, vomiting
  • diarrhoea
  • flatulence
  • abdominal pain
General
  • headache
  • fatigue
  • altered sensation in your mouth
  • dizziness
Skin related
  • rash
Occasionally the skin rash may be severe and as a result your doctor may decide that you have to stop taking this medicine
Musculoskeletal:
  • muscle pain
  • tenderness and weakness
These side effects have been reported with antiretroviral therapy including protease inhibitors and nucleoside analogues.		Speak to your doctor if you have any of these less serious side effects and they worry you.

In some individuals, treatment with a combination of antiretroviral medicines that includes a protease inhibitor may find their body shape changes due to an increase in body fat. It is not yet known what causes these changes, or whether they have any long-term effects on your health. If you notice changes in your body shape, speak to your doctor.

Your doctor will ask you to undertake blood tests regularly to monitor for any abnormalities (blood lipids and blood sugar). Increases in liver enzymes and blood fats have been reported in patients taking TELZIR and ritonavir.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What TELZIR contains

Active ingredient
(main ingredient)		Fosamprenavir as fosamprenavir sodium
Other ingredients
(inactive ingredients)		croscarmellose sodium
colloidal silicon dioxide
magnesium stearate
microcrystalline cellulose
povidone K30
The tablet coating contains:
glycerol triacetate
hypromellose
iron oxide red (E172)
titanium dioxide (E171)

Do not take this medicine if you are allergic to any of these ingredients.

What TELZIR looks like

TELZIR tablets are pink, film-coated, capsule-shaped, biconvex tablets, debossed GX LL7 on one face (AUST R 101604). They are available in bottles of 60 tablets.

Who distributes TELZIR

ViiV Healthcare Pty Ltd
Level 4, 436 Johnson Street
Abbotsford VIC 3067
Australia

Licenced from Vertex Pharmaceuticals Inc., Cambridge MA 02139 USA.

Trademarks are owned by or licenced to the ViiV Healthcare group of companies.

© 2022 ViiV Healthcare group of companies or its licensor.

This leaflet was prepared in November 2022.

Version 13.0

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Telzir

Active ingredient

Fosamprenavir

Schedule

S4

 

1 Name of Medicine

Fosamprenavir calcium.

2 Qualitative and Quantitative Composition

Each Telzir tablet contains 700 mg of fosamprenavir, as fosamprenavir calcium.
Fosamprenavir is converted in humans to amprenavir. Each Telzir 700 mg tablet is equivalent to approximately 600 mg of amprenavir.
Fosamprenavir calcium is a white to cream coloured solid.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Telzir are biconvex, capsules-shaped, pinked coloured tablets marked with GXLL7 on one face.

4 Clinical Particulars

4.1 Therapeutic Indications

Telzir, in combination with low dose ritonavir, is indicated for the treatment of Human Immunodeficiency Virus Type 1 (HIV-1) infected adults, adolescents and children of 6 years and above in combination with other antiretroviral medicinal products.
In antiretroviral experienced adults Telzir in combination with low dose ritonavir has not been shown to be as effective as lopinavir/ritonavir. No comparative studies have been undertaken in children or adolescents.

4.2 Dose and Method of Administration

A physician experienced in the management of HIV infection should initiate therapy.
Fosamprenavir is administered orally.
The tablet can be taken with or without food.
Higher than approved dose combinations of fosamprenavir with ritonavir are not recommended for use (see Section 4.4 Special Warnings and Precautions for Use).

Adults (greater than or equal to 18 years of age).

Antiretroviral naive patients.

The recommended dose is 1400 mg fosamprenavir once daily with 200 mg ritonavir once daily or 700 mg (one tablet) fosamprenavir twice daily with 100 mg ritonavir twice daily. Both regimens must be administered in combination with other antiretroviral agents.

Protease inhibitor experienced patients.

The recommended dose 700 mg (one tablet) fosamprenavir twice daily with 100 mg ritonavir twice daily. This regimen must be administered in combination with other antiretroviral agents.
The once daily administration of fosamprenavir plus ritonavir is not recommended in protease inhibitor experienced patients.
Each Telzir 700 mg tablet is equivalent to approximately 600 mg of amprenavir.

Children and adolescent patients (6-18 years of age).

The tablet regimens of fosamprenavir 700 mg twice daily plus 100 mg ritonavir twice daily (for protease inhibitor naïve or experienced patients) may be used in children and adolescents if they weigh at least 39 kg and can swallow the tablets whole.
The tablet can be taken with or without food.

Children (less than 6 years of age).

The safety and efficacy of fosamprenavir in combination with ritonavir has not yet been established in this patient population (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Elderly.

The pharmacokinetics of fosamprenavir in combination with ritonavir has not been studied in patients over 65 years of age (see Section 5.2 Pharmacokinetic Properties).

Renal impairment.

No initial dose adjustment is considered necessary in patients with renal impairment (see Section 5 Pharmacological Properties).

Hepatic impairment.

Fosamprenavir is converted in man to amprenavir. The principal route of amprenavir and ritonavir elimination is hepatic metabolism.

For adults with mild hepatic impairment (C-P score: 5-6).

Fosamprenavir should be used with caution and at a reduced dose of 700 mg fosamprenavir twice daily with 100 mg ritonavir once daily.

For adults with moderate (C-P score 7-9) or severe (C-P score 10-15) hepatic impairment.

Use of fosamprenavir is not recommended as the reduced dose required in hepatic impairment cannot be achieved using the 700 mg tablet. Alternative options should be considered.
Even with these dose adjustments for adults with hepatic impairment, some subjects may have higher than anticipated amprenavir and ritonavir plasma concentrations due to inter-patient variability, therefore appropriate laboratory tests for liver function should be conducted prior to initiating therapy and at periodic intervals during treatment (see Section 4.4 Special Warnings and Precautions for Use).
No dose recommendation can be made for children (2 years to less than 12 years of age) and adolescents (12 to 17 years of age) with hepatic impairment.

4.3 Contraindications

Known hypersensitivity to fosamprenavir, amprenavir and ritonavir or to any of the excipients of these medicinal products.
Fosamprenavir in combination with ritonavir must not be administered concurrently with medicinal products with narrow therapeutic windows that are substrates of cytochrome P450 3A4 (CYP3A4). Co-administration may result in competitive inhibition of the metabolism of these medicinal products and create the potential for serious and/or life threatening adverse events such as cardiac arrhythmia (for example, astemizole, terfenadine, cisapride, pimozide), hypotension (for example, the alpha blocker alfuzosin), prolonged sedation or respiratory depression (for example, triazolam, midazolam, quetiapine) or peripheral vasospasm or ischaemia (for example, ergotamine, dihydroergotamine and ergometrine) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Fosamprenavir/ritonavir must not be administered concomitantly with the antipsychotic medicinal product lurasidone. Please refer to the full prescribing information for ritonavir for other potential drug interactions (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Fosamprenavir/ritonavir must not be administered concomitantly with sildenafil when used for the treatment of pulmonary arterial hypertension (for use of sildenafil in patients with erectile dysfunction, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). There is increased potential for sildenafil associated serious adverse events.
Ritonavir also inhibits CYP2D6 in vitro and in vivo but to a lesser extent than CYP3A4. Fosamprenavir in combination with ritonavir should not be co-administered with medicinal products that are highly dependent on CYP2D6 metabolism and for which elevated plasma concentrations are associated with serious and/or life threatening results. These medicinal products include flecainide and propafenone (please refer to the full prescribing information of ritonavir for further details) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Fosamprenavir in combination with ritonavir must not be administered concurrently with rifampicin due to expected large decreases in plasma concentrations of amprenavir (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

General.

Patients should be advised that fosamprenavir in combination with ritonavir, or any other current antiretroviral therapy does not cure HIV, they may still develop opportunistic infections, and other complications of HIV infection. Current antiretroviral therapies, including fosamprenavir/ritonavir combinations, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.
Fosamprenavir contains a sulphonamide moiety. The potential for cross sensitivity between drugs in the sulphonamide class and fosamprenavir is unknown. In the pivotal studies of fosamprenavir, there was no evidence of an increased risk of rashes in patients with a history of sulphonamide allergy that received fosamprenavir versus those who received fosamprenavir and did not have a sulphonamide allergy. Yet, the fosamprenavir/ritonavir combination should be used with caution in patients with a known sulphonamide allergy.
Co-administration of Telzir 700 mg twice daily with ritonavir in doses greater than 100 mg twice daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile of the combination and therefore is not recommended.
Use of fosamprenavir with ritonavir at higher than approved dosages has resulted in elevated transaminase levels in some subjects and are not recommended for use.

Hepatitis C virus (HCV) direct acting antivirals.

When hepatitis C virus direct acting antiviral (DAA) drugs, which are metabolised by CYP3A4 or are inducers/inhibitors of CYP3A4, are co-administered with fosamprenavir/ritonavir, altered plasma concentrations of medications are expected due to inhibition or induction of CYP3A4 enzyme activity. These interactions may lead to:
clinically significant adverse reactions from greater exposures of fosamprenavir/ritonavir or concomitant medications;
loss of therapeutic effect of fosamprenavir/ritonavir or concomitant medications and possible development of resistance.
Therefore, co-administration of fosamprenavir/ritonavir is not recommended with HCV DAA drugs, which are metabolised by CYP3A4 or are inducers/inhibitors of CYP3A4, because of the potential for an interaction (for example telaprevir, boceprevir, simeprevir, paritaprevir). In case of concomitant HCV DAA therapy for hepatitis C, please refer to the relevant product information for these medications.

Rash/cutaneous reactions.

Most patients with mild or moderate rash can continue the fosamprenavir. Appropriate antihistamines (e.g. cetirizine dihydrochloride) may reduce pruritus and hasten the resolution of rash. Severe and life threatening skin reactions, including Stevens-Johnson syndrome, were reported in less than 1% of subjects included in the clinical development programme. Fosamprenavir should be permanently discontinued in case of severe rash, or in case of rash of moderate intensity with systemic or mucosal symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)).

Haemophilia.

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthroses in haemophiliac patients type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued, or reintroduced if treatment had been discontinued. A causal relationship has been evoked, although the mechanism of action has not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Hyperglycaemia.

New onset of diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus have been reported in patients receiving antiretroviral therapy, including protease inhibitors. Some patients required either initiation or dose adjustments of insulin or oral hypoglycaemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. A causal relationship between protease inhibitor therapy and these events has not been established.

Body fat changes.

Combination antiretroviral therapy, including regimens containing a protease inhibitor, may be associated with increased body fat in some patients. A causal relationship has not been established.

Lipid elevations.

Treatment with fosamprenavir has resulted in increases in the concentration of triglycerides and cholesterol. Triglyceride and cholesterol testing should be performed prior to initiating therapy with fosamprenavir and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.

Immune reconstitution syndrome.

In HIV infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Information for patients.

Patients should be advised that Telzir, or any other current antiretroviral therapy, does not cure HIV. Patients may still develop opportunistic infections and other complications of HIV infection. Current antiretroviral therapies, including Telzir, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Use in hepatic impairment.

Amprenavir and ritonavir are both principally metabolised by the liver. Fosamprenavir with ritonavir should be used with caution and at reduced doses in adults with mild, moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration). Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk of developing transaminase elevations. Appropriate laboratory testing should be conducted prior to initiating therapy and at periodic intervals during treatment.

Use in renal impairment.

Since the renal clearance of amprenavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because amprenavir and ritonavir are highly protein bound, it is unlikely that haemodialysis or peritoneal dialysis will significantly remove them.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

Children (0-6 years of age).

The pharmacokinetics safety and efficacy of fosamprenavir in children below 6 years of age has not yet been fully established (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Children and adolescent patients (6-18 years of age).

Fosamprenavir tablets may be used in children and adolescents if they weigh at least 39 kgs and can swallow the tablets whole (see Section 4.2 Dose and Method of Administration).
If vomiting occurs within 30 minutes after dosing, the dose should be repeated.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Table 8.

4.5 Interactions with Other Medicines and Other Forms of Interactions

(See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Both amprenavir the active metabolite of fosamprenavir and ritonavir are inhibitors of the cytochrome P450 3A4 enzyme (CYP3A4). Consequently, fosamprenavir in combination with ritonavir may increase plasma levels of medicines that have a narrow therapeutic window and are substrates of CYP3A4 and should not be administered concurrently. Other medicinal products that are inducers, inhibitors or substrates of CYP3A4 may also result in serious and/or life threatening drug interactions. Caution is, therefore, advised whenever fosamprenavir in combination with ritonavir is co-administered with such products (see Section 4.3 Contraindications).
Co-administration of fosamprenavir/ritonavir with other antineoplastics metabolised by CYP3A (for example dasatinib, nilotinib, ibrutinib, vinblastine and everolimus) may increase concentrations of these medicinal products, potentially increasing the risk of adverse events usually associated with these agents. Please refer to the relevant product information for these medications.
Co-administration of fosamprenavir and ritonavir with halofantrine is not recommended as halofantrine concentrations may be increased, potentially increasing the risk of serious adverse effects such as cardiac arrhythmia.
The HMG-CoA reductase inhibitors lovastatin and simvastatin are highly dependent on CYP3A4 for metabolism, thus concomitant use of fosamprenavir and ritonavir with simvastatin or lovastatin is not recommended due to an increased risk of myopathy, including rhabdomyolysis. Caution must also be exercised if fosamprenavir and ritonavir are used concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A4. In this situation, a reduced dose of atorvastatin should be considered. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin are recommended.
Concomitant use of fosamprenavir with ritonavir and fluticasone propionate or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression.
Although the isozyme(s) responsible for bepridil metabolism has (have) not been elucidated, the metabolic pathways primarily responsible for bepridil metabolism are mediated by the CYP450 enzyme system. Because amprenavir and ritonavir are inhibitors of the CYP3A4 isozyme, the CYP450 isozyme most commonly responsible for drug metabolism, and because increased plasma bepridil exposure may increase the risk of life threatening arrhythmia, caution is warranted when amprenavir and bepridil are co-administered.
Serious and/or life threatening drug interactions could occur between amprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, quinidine and warfarin. Concentration monitoring (warfarin, monitor International Normalised Ratio) of these agents is recommended as this should minimise the risk of potential safety problems with concomitant use.
Concomitant use of PDE5 inhibitors (e.g. sildenafil) for the treatment of erectile dysfunction in patients receiving the fosamprenavir/ritonavir combination is not recommended. Concomitant use of fosamprenavir and ritonavir with PDE5 inhibitors is expected to substantially increase PDE5 inhibitor concentrations and may result in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes and priapism.
Co-administration of amprenavir with rifabutin results in a 200% increase in rifabutin plasma concentrations (AUC). When ritonavir is co-administered a larger increase in rifabutin concentrations is expected. A reduction of rifabutin dosage of at least 75% the recommended dose is recommended when administered with fosamprenavir and ritonavir and patients clinically monitored.
Concomitant use of the fosamprenavir/ritonavir combination and products containing Hypericum perforatum (also known as St. John's wort) is not recommended. A pharmacokinetic study with indinavir indicates that Hypericum perforatum may reduce amprenavir and/or ritonavir serum concentrations when administered concomitantly.
Because there may be an increased risk of hepatic transaminase elevations and hormonal levels may be altered with co-administration of fosamprenavir, ritonavir and oral contraceptives, alternative non-hormonal methods of contraception are recommended for women of childbearing potential.
No data are available on the co-administration of fosamprenavir and ritonavir with oestrogens and/or progestogens when used as hormonal replacement therapies. The efficacy and safety of these therapies with fosamprenavir and ritonavir has not been established.
Fosamprenavir/ritonavir must not be administered concomitantly with sildenafil when used for the treatment of pulmonary arterial hypertension. There is increased potential for sildenafil associated serious adverse events (see Section 4.3 Contraindications).
Ritonavir, as well as being a potent inhibitor of CYP3A4, is also an inhibitor of CYP2D6 and an inducer of CYP1A2, CYP2C9 and glucuronosyl transferase. Fosamprenavir in combination with ritonavir should not be co-administered with medicinal products that are highly dependent on CYP2D6 metabolism and for which elevated plasma concentrations are associated with serious and/or life threatening results. These medicinal products include flecainide and propafenone (see Section 4.3 Contraindications). The full prescribing information of Norvir (ritonavir) should be referred to prior to undertaking the dosing regimen of fosamprenavir and ritonavir.
When fosamprenavir and ritonavir are co-administered, the ritonavir metabolic drug interaction profile may predominate because ritonavir is a more potent CYP3A4 inhibitor. The full prescribing information for ritonavir must therefore be consulted prior to initiation of therapy with fosamprenavir and ritonavir.
Interaction studies have only been performed in adults.

Interactions involving CYP3A4.

The medications listed below include examples of substrates, inhibitors, or inducers of CYP3A4 that could interact with fosamprenavir in combination with ritonavir when used concomitantly. This list is not exhaustive. In some cases the clinical significance of these potential interactions is unknown and has not been studied. Patients should therefore be monitored for toxicities associated with such medicines when they are used in combination with fosamprenavir and ritonavir.

Interactions involving CYP2D6.

Ritonavir is an inhibitor of CYP2D6. Therefore fosamprenavir in combination with ritonavir may result in increased plasma concentrations of medicinal products that are primarily metabolised by CYP2D6 (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Additional associations, precautions for use.

Drug interaction studies were performed with Telzir and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration on AUC, Cmax and Cmin values are summarised in Table 1 (effect of other drugs on amprenavir) and Table 3 (effect of Telzir on other drugs). In addition, since Telzir delivers comparable amprenavir plasma concentrations as Agenerase, drug interaction data derived from studies with Agenerase are provided in Tables 2 and 4. For information regarding clinical recommendations, see Tables 5 and 6.

Antiretroviral agents.

Non-nucleoside reverse transcriptase inhibitors.

Nevirapine.

The AUC and Cmin of amprenavir were decreased by 11% and 19%, respectively, with Cmax unchanged when fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily) was given concomitantly with nevirapine (200 mg twice daily). The AUC, Cmax and Cmin of nevirapine were increased by 14%, 13% and 22%, respectively. Therefore, if nevirapine is given in combination with fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily), no dose adjustment is necessary. The fosamprenavir with ritonavir once daily regimen has not been studied.

Delavirdine.

No dose recommendations can be given for the co-administration of the fosamprenavir/ritonavir combination and delavirdine.
Nucleoside/nucleotide reverse transcriptase inhibitors. No dose adjustment is considered necessary when the following antiretroviral agents are co-administered with fosamprenavir: zidovudine, didanosine, stavudine, lamivudine, abacavir and tenofovir.
Protease inhibitors. No dose recommendation can be given for the use of fosamprenavir and ritonavir in combination with other protease inhibitors. Available interaction data are presented in Tables 1-4.

Atazanavir.

Co-administration of fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily) with atazanavir (300 mg once daily) for 10 days had no effect on steady-state plasma amprenavir pharmacokinetics. Atazanavir plasma AUC(0-T) decreased by 22%, Cmax by 24% and CT remained unchanged relative to values obtained from atazanavir (300 mg once daily) plus ritonavir (100 mg once daily).
Integrase inhibitors.

Raltegravir.

There is potential for a pharmacokinetic interaction with co-administration of fosamprenavir/ritonavir 700/100 mg twice daily and raltegravir 400 mg twice daily. This may lead to reductions in the Cmin of both medicinal products. The clinical significance of these reductions is unknown.

Dolutegravir.

Amprenavir pharmacokinetics were unchanged following co-administration of fosamprenavir/ritonavir 700/100 mg twice daily with dolutegravir 50 mg once daily. Dolutegravir AUC(0-T), Cmax, and CT were reduced by 35%, 24%, and 49%, respectively, when combined fosamprenavir/ritonavir. No dosage adjustment of fosamprenavir or dolutegravir is recommended based on observed exposure response relationships of clinical data. Caution is warranted and clinical monitoring is recommended when these combinations are given in integrase inhibitor resistant patients.
CCR5-receptor antagonists.

Maraviroc.

A decrease in amprenavir C12h of 36% was observed when fosamprenavir 700 mg and ritonavir 100 mg twice daily were co-administered with maraviroc 300 mg twice daily and a decrease in amprenavir C24h of 15% when fosamprenavir 1400 mg and ritonavir 100 mg once daily were co-administered with maraviroc 300 mg once daily (see Table 1). Clinical studies showed comparable efficacy between fosamprenavir/ritonavir with maraviroc 150 mg twice daily and other boosted PIs with maraviroc 150 mg twice daily. Maraviroc exposures are increased by approximately 2-fold when administered with fosamprenavir/ritonavir (see Table 3). If fosamprenavir/ritonavir is co-administered with maraviroc, the recommended dose of maraviroc is 150 mg twice daily. No dosage adjustment is required for fosamprenavir with ritonavir.

Antihepatitis C medicinal products.

Telaprevir.

Concomitant administration of fosamprenavir with ritonavir and telaprevir results in reduced steady-state exposure to both amprenavir and telaprevir. The mechanism of interaction is unknown. Concomitant administration of fosamprenavir with ritonavir and telaprevir is not recommended.

Antibiotics/antifungals.

Clarithromycin.

Ritonavir increases plasma concentrations of clarithromycin. A reduction in the clarithromycin dose should be considered when co-administered with fosamprenavir and ritonavir in patients with renal impairment.

Erythromycin.

No pharmacokinetic study has been performed with fosamprenavir in combination with erythromycin, however, plasma levels of both medicinal products may be increased when co-administered.

Ketoconazole/itraconazole.

Amprenavir and ritonavir both increase plasma concentrations of ketoconazole and are expected to increase itraconazole concentrations. High doses of ketoconazole and itraconazole (> 200 mg/day) should not be used concomitantly with fosamprenavir and ritonavir without assessing the risk/benefit ratio and increased monitoring for adverse events due to ketoconazole and itraconazole.

Rifabutin.

Co-administration of amprenavir with rifabutin results in a 200% increase in rifabutin plasma concentrations (AUC) and an increase of rifabutin related adverse events. When ritonavir is co-administered a larger increase in rifabutin concentrations may occur. A reduction of rifabutin dosage of at least 75% the recommended dose is recommended when administered with fosamprenavir and ritonavir. Further dose reduction may be necessary (see Section 4.4 Special Warnings and Precautions for Use).

Rifampicin.

Co-administration with Telzir may lead to loss of virologic response and possible resistance to Telzir or to the class of protease inhibitors.

Other medicinal products.

Antacids.

No dose adjustment for any of the respective medicinal products is considered necessary when administered concomitantly.

Histamine H2-receptor antagonist.

No dose adjustment for any of the respective medicinal products is considered necessary when administered concomitantly.

Proton pump inhibitors.

Co-administration of esomeprazole (20 mg once daily) with fosamprenavir (700 mg twice daily) in combination with ritonavir (100 mg twice daily) for 14 days did not alter plasma amprenavir AUC, Cmax or Cmin and did not alter plasma esomeprazole AUC or Cmax; esomeprazole Tmax was delayed 1 hour. No dose adjustment for any of the respective medicinal products is considered necessary when administered concomitantly.
For some substances that can cause serious or life threatening adverse experiences, such as amiodarone, quinidine, lidocaine (by systemic route), tricyclic antidepressants and warfarin (monitor INR), plasma concentration monitoring is available. For these medicinal products, concentration monitoring should reduce the potential for safety problems with concomitant use with fosamprenavir and ritonavir.

Anticonvulsant drugs.

Phenytoin. The AUC and Cmin of amprenavir were increased by 20% and 19%, respectively, with Cmax unchanged when fosamprenavir (700 mg twice daily) plus ritonavir (100 mg twice daily) was given concomitantly with phenytoin (300 mg once daily). The AUC, Cmax and Cmin of phenytoin were decreased by 22%, 20% and 29% respectively. Therefore, if fosamprenavir plus ritonavir is given in combination with phenytoin, no change to the fosamprenavir plus ritonavir dosage regimen is required. However, it is recommended that phenytoin plasma concentrations be monitored and phenytoin dose increased as appropriate. The fosamprenavir with ritonavir once daily regimen has not been studied.

Other anticonvulsants.

Concomitant administration of other anticonvulsant agents known as enzymatic inducers (e.g. phenobarbitone and carbamazepine) has not been studied but may lead to a decrease in the plasma concentrations of amprenavir.

Benzodiazepines.

Alprazolam, clorazepate, diazepam and flurazepam: serum concentrations may be increased, which could increase their activity (see Section 4.3 Contraindications).

Calcium channel blockers.

Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine and verapamil: serum concentrations of these medicines may be increased, which could increase their activity and toxicity.

Dexamethasone.

May induce CYP3A4 and decrease plasma concentrations of amprenavir.

PDE5 inhibitors.

Based on data for ritonavir and other protease inhibitors, plasma concentrations of PDE5 inhibitors (e.g. sildenafil) are expected to substantially increase when co-administered with fosamprenavir and ritonavir and may result in an increase in PDE5 inhibitor associated adverse events. Concomitant use of PDE5 inhibitors for the treatment of erectile dysfunction or pulmonary arterial hypertension is not recommended. Concomitant use of fosamprenavir/ritonavir is contraindicated in patients being treated with sildenafil for pulmonary arterial hypertension (see Section 4.3 Contraindications).
Fosamprenavir/ritonavir must not be administered concomitantly with sildenafil when used for the treatment of pulmonary arterial hypertension. There is increased potential for sildenafil associated serious adverse events (see Section 4.3 Contraindications).

Fluticasone propionate (interaction with ritonavir).

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this interaction is also expected with other corticosteroids metabolised via the P450 3A pathway (see Section 4.4 Special Warnings and Precautions for Use).
Therefore, concomitant use of fluticasone propionate and ritonavir should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.

Halofantrine.

Plasma concentrations of halofantrine may increase when co-administered with fosamprenavir and ritonavir and may result in an increase in halofantrine associated adverse events, such as cardiac arrhythmia. Concomitant use is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

HMG-CoA reductase inhibitors.

HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 for metabolism, such as atorvastatin, lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with fosamprenavir and ritonavir. Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with fosamprenavir and ritonavir is not recommended.
When used with fosamprenavir and ritonavir, doses of atorvastatin no greater than 20 mg/day should be administered, with careful monitoring for atorvastatin toxicity. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with protease inhibitors. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see Section 4.4 Special Warnings and Precautions for Use).

Immunosuppressants.

Plasma concentrations of cyclosporin, rapamycin and tacrolimus may be increased when co-administered with fosamprenavir and ritonavir. Therefore, frequent therapeutic concentration monitoring is recommended until levels have stabilised.

Methadone.

Co-administration of fosamprenavir 700 mg and ritonavir 100 mg twice daily with methadone once daily (≤ 200 mg) for 14 days decreased the active (R-) methadone enantiomer AUC(0-T) and Cmax by 18% and 21%. Unbound fraction of R-methadone was increased at 2 hours (12.4% vs. 8.5%) and 6 hours (11.5% vs. 9.3%), but plasma unbound R-methadone (active) concentrations at 2 hours and 6 hours were not significantly altered. Based on historical comparison, methadone did not appear to alter plasma amprenavir pharmacokinetic parameters. Similar effects on methadone concentrations were observed when amprenavir (without ritonavir) and methadone were co-administered. On the basis of these data no dose adjustment is necessary when fosamprenavir/ritonavir is co-administered with methadone.

Paroxetine.

Plasma concentrations of paroxetine may be significantly decreased when co-administered with fosamprenavir and ritonavir. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy).

Steroids.

Co-administration of fosamprenavir 700 mg twice daily + ritonavir 100 mg twice daily with Brevinor (ethinly estradiol (EE) 0.035 mg/norethisterone (NE) 0.5 mg) once daily decreased plasma EE AUC(0-T) and Cmax by 37% and 28%, respectively, and decreased plasma NE AUC(0-T), Cmax, and CT by 34%, 38% and 26%, respectively. Steady-state plasma amprenavir pharmacokinetic (PK) parameters were not significantly affected by co-administration with Brevinor; however, ritonavir AUC(0-T) and Cmax were 45% and 63% higher, respectively, compared to historical data in female subjects dosed with fosamprenavir/ritonavir alone. In addition to the decreased hormonal contraceptive exposures, co-administration of fosamprenavir with ritonavir and Brevinor resulted in clinically significant hepatic transaminase elevations in some healthy subjects. Therefore, alternative nonhormonal methods of contraception are recommended for women of childbearing potential (see Section 4.4 Special Warnings and Precautions for Use).

St. John's wort.

Serum levels of amprenavir can be reduced by concomitant use of the herbal preparation St. John's wort (Hypericum perforatum) (see Section 4.4 Special Warnings and Precautions for Use).

Antineoplastic agents.

When antineoplastic agents (for example dasatinib, nilotinib, ibrutinib, vinblastine and everolimus) that are metabolised by CYP3A are co-administered with fosamprenavir with/without ritonavir, plasma concentrations of these antineoplastic medications may be increased and could increase the risk of adverse events usually associated with these antineoplastic agents. In case of concomitant administration with antineoplastic agents metabolized by CYP3A, please refer to the relevant product information for these medications.

Antipsychotics.

Quetiapine: Due to CYP3A inhibition by fosamprenavir, concentrations of quetiapine are expected to increase. Concomitant administration of fosamprenavir and quetiapine is contraindicated as it may increase quetiapine related toxicity. Increased plasma concentrations of quetiapine may lead to coma.
Lurasidone: Concomitant administration of fosamprenavir/ritonavir with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions (see Section 4.3 Contraindications).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility in male and female rats was unaffected by oral fosamprenavir dose resulting in systemic exposures (plasma AUC) to amprenavir that were similar to that seen in humans treated with the maximum recommended dose of fosamprenavir in combination with ritonavir.
(Category B3)
Embryofoetal development was unaffected by oral treatment of pregnant rats and rabbits with fosamprenavir during the period of organogenesis. Systemic plasma exposure (AUC) to amprenavir in these studies was similar (rats) or lower (rabbits) than exposure in patients in clinical studies with fosamprenavir. In view of the low exposure in rabbits, the potential developmental toxicity of fosamprenavir has not been fully determined.
Placental transfer of amprenavir has been observed following administration of fosamprenavir/ritonavir 700/100 mg twice daily to pregnant women (see Section 5.2 Pharmacokinetic Properties, Special populations, Pregnancy). As of 31st July 2017, fosamprenavir has been evaluated in the Antiretroviral Pregnancy Registry (APR) in 157 women and included 120 exposures during the first trimester and 36 exposures during the second/third trimester; with 4 birth defects reported in live born infants. However, there are no adequate and well controlled trials in pregnant women and the safe use of fosamprenavir in human pregnancy has not been established. Limited data on the use of fosamprenavir during pregnancy from the APR and case reports are not sufficient to inform a drug-associated risk of birth defects and miscarriage.
Fosamprenavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
 Health experts recommend that where possible HIV infected women do not breast feed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breast feeding during antiretroviral therapy. It is expected that amprenavir may be secreted into human milk based on animal data. There is no information on the transfer or effects of amprenavir on the breastfed infant or the effects of the drug on milk production.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of fosamprenavir in combination with ritonavir on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

The safety of fosamprenavir in combination with ritonavir has been studied in adults in controlled clinical trials (n = 534), in combination with various other antiretroviral agents. The most frequently (> 5% of adult subjects treated) reported undesirable effects were gastrointestinal events (nausea, diarrhoea, abdominal pain and vomiting) and headache. Most undesirable effects associated with fosamprenavir/ritonavir combination therapies were mild to moderate in severity, early in onset and rarely treatment limiting. For many of these events, it is unclear whether they are related to the fosamprenavir/ritonavir combination, to concomitant treatment used in the management of HIV disease or to the disease process.
Table 7 summarises the most common (≥ 2%) grade 2-4 drug related adverse events reported in all subjects enrolled in APV30002 or APV30003 while receiving randomised therapy.
In antiretroviral naïve patients (APV30002) receiving Telzir/ritonavir in combination with abacavir and lamivudine, drug hypersensitivity was commonly# reported. All cases were reported as possibly related to abacavir. In cases of reported drug hypersensitivity, abacavir was discontinued and an alternative antiretroviral drug substituted. Few patients withdrew from the study due to these events. (#: Common defined as ≥ 1%, < 10%.)

Nervous system disorders.

Common: dizziness, headache and oral paraesthesia.

Gastrointestinal disorders.

Common: diarrhoea, nausea, vomiting, abdominal pain and flatulence.

Metabolism and nutrition disorders.

Very common: hypercholesterolaemia.
Common: hypertriglyceridaemia.
New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus have been reported in patients receiving antiretroviral protease inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac disorders.

Uncommon: myocardial infarction.

Skin and subcutaneous tissue disorders.

Common: rash/cutaneous reactions. Erythematous or maculopapular cutaneous eruptions, with or without pruritus, may occur during therapy. The rash generally will resolve spontaneously without the necessity of discontinuing treatment with the fosamprenavir/ritonavir combination. Fosamprenavir/ritonavir combination therapy should be definitively stopped in case of severe rash or in case of rash of slight or moderate intensity associated with systemic or mucosal signs (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon: angioedema.
Rare: Stevens-Johnson syndrome (severe or life threatening cases of rash).

Renal and urinary disorders.

Uncommon: renal stones.

Lipohypertrophy.

In some patients, an increase in body fat (lipohypertrophy) has been reported with anti-retroviral regimens containing a protease inhibitor. Metabolic abnormalities including hypertriglyceridaemia, hypercholesterolaemia, resistance to insulin and hyperglycaemia have also been reported with protease inhibitors containing regimen. (See Section 4.4 Special Warnings and Precautions for Use).

Musculoskeletal and connective tissue disorders.

An increase in CPK, myalgia, myositis, and rarely, rhabdomyolysis, have been reported with protease inhibitors, more specifically in association with nucleoside analogues.
There have been reports of increased spontaneous bleeding in haemophiliac patients receiving antiretroviral protease inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Immune system disorders.

Immune reactivation syndrome (in HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise).

Osteonecrosis.

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.

Children and adolescents.

The adverse event profile in children and adolescents is based on integrated safety data from two studies (APV29005 and APV20003) in which 126 HIV-1 infected subjects 2 to 18 years of age received fosamprenavir with ritonavir with background nucleoside reverse transcriptase inhibitor therapy (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Overall the safety profile in children and adolescents was comparable to that seen in adults.
Clinical laboratory abnormalities (grade 3 or 4) potentially related to treatment with Telzir in combination with ritonavir and reported in greater than or equal to 2% of adult subjects are provided in Table 8.
Routine pharmacovigilance identified oral paraesthesia with fosamprenavir as a safety signal. A review of the key clinical trials for fosamprenavir revealed a trend towards oral paraesthesia (and related AEs), with a frequency category of common (> 1% - < 10%).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no known antidote for fosamprenavir. Since amprenavir is highly protein bound, dialysis is unlikely to be helpful in reducing blood levels. If overdose occurs, the patient should be monitored for evidence of toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)) and standard supportive treatment applied as necessary.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

The nonclinical statements were consistent with those in the amprenavir product information, or were supported by limited experiments with fosamprenavir.

5.1 Pharmacodynamic Properties

Mechanism of action.

Fosamprenavir calcium is a prodrug of amprenavir. It is the monocalcium salt of the phosphate ester of amprenavir and is hydrolysed to inorganic phosphate and the active metabolite amprenavir as it is absorbed through the gut epithelium. Amprenavir is a nonpeptide competitive inhibitor of the HIV protease. It blocks the ability of the viral protease to cleave the precursor polyproteins necessary for viral replication. Fosamprenavir has been shown to have little or no antiviral activity or enzyme inhibition properties in vitro. Any inhibition observed with fosamprenavir in these studies is considered to be due to trace amounts of amprenavir.
Fosamprenavir requires metabolism in vivo to generate the active moiety, amprenavir. In the absence of in vivo metabolism, fosamprenavir has negligible activity in in vitro enzymatic and antiviral assays, and therefore such assays are performed using amprenavir.
Amprenavir is a potent and selective inhibitor of HIV-1 and HIV-2 replication in vitro. In isolated experimental settings, synergy was shown in vitro in combination with nucleoside analogues including didanosine, zidovudine, abacavir and the protease inhibitor, saquinavir. It has been shown to have an additive effect in combination with indinavir, ritonavir and nelfinavir.
Co-administration of ritonavir with fosamprenavir (at fosamprenavir/ritonavir doses of 700/100 mg twice daily or 1400/200 mg once daily) increased plasma amprenavir AUC by approximately 2-fold and plasma CT,ss by 4 to 6-fold, compared to values obtained when fosamprenavir (at a dose of 1400 mg twice daily) is administered alone. Both fosamprenavir/ritonavir combination regimens (700/100 mg twice daily and 1400/200 mg once daily) maintain plasma amprenavir concentrations above the mean IC50 values for amprenavir against HIV for patients spanning the range from PI-naive (mean protein binding adjusted IC50 = 0.146 microgram/mL) to heavily PI experienced (mean protein binding adjusted IC50 = 0.90 microgram/mL).

Resistance in vitro.

Serial passage experiments have demonstrated the protease mutation I50V to be key to the development of amprenavir resistance in vitro, with the triple variant, I50V+M46I/L+I47V, resulting in a greater than 10-fold increase in IC50 to amprenavir. This triple mutation resistance profile has not been observed with other protease inhibitors either from in vitro studies or in clinical settings. In vitro variants resistant to amprenavir remained sensitive to saquinavir, indinavir and nelfinavir, but showed three to fivefold reduced susceptibility to ritonavir. The triple mutant, I50V+M46I/L+I47V, was unstable during in vitro passage in the presence of saquinavir, with loss of the I47V mutation, and the development of resistance to saquinavir resulted in resensitisation to amprenavir. Passage of the triple mutant in either indinavir, nelfinavir or ritonavir resulted in additional protease mutations being selected, leading to dual resistance. Mutation I84V, observed transiently in vitro has rarely been selected during amprenavir therapy. Additional recent data from in vitro passage experiments have also identified the selection by amprenavir of protease mutations I54M and V32I+I47V.

Resistance in vivo: protease inhibitor naive subjects.

The resistance profile seen with amprenavir in clinical practice is different from that observed with other protease inhibitors. Consistent with the first in vitro experiments, the development of amprenavir resistance during therapy is, in many cases, associated with the mutation I50V. However, the three alternative mechanisms observed during in vitro passage experiments have also been observed to result in the development of resistance during the use of amprenavir in the clinic. Development of resistance to amprenavir during therapy may involve either mutations I50V or I54L/M or V32I+I47V or, rarely, I84V. Each of the four genetic patterns may be accompanied by additional secondary mutations, in particular M46I/L, and produces viruses with reduced susceptibility to amprenavir, some cross resistance to ritonavir, but susceptibility to indinavir, nelfinavir and saquinavir is retained.
The following summarises the mutations associated with the development of reduced phenotypic susceptibility to amprenavir in subjects treated with amprenavir.
Protease mutations acquired on amprenavir containing therapy which have been demonstrated to result in reduced phenotypic susceptibility to amprenavir: I50V or I54L/M or I84V or V32I with I47V.
In treatment naive subjects, significant differences were observed with respect to the emergence of resistance to both the PI and NRTI components of the study regimens between those subjects who received fosamprenavir/ritonavir in combination and those who received fosamprenavir without ritonavir as well as with those who received nelfinavir.
Treatment emergent NRTI resistance was significantly less frequent with fosamprenavir/ritonavir treated subjects (4/32, 13%) compared to the nelfinavir treated subjects (31/54, 57%) (p < 0.001).
The incidence of treatment emergent protease mutations (PRO mutations) associated with resistance to amprenavir was significantly lower in subjects who received fosamprenavir/ritonavir once daily (0/32, 0%) compared with fosamprenavir twice daily without ritonavir (5/29, 17%) and was lower than PRO mutations associated with resistance to nelfinavir treated patients (17/54, 31%).
Treatment emergence of NRTI resistance was also less frequent with fosamprenavir/ritonavir treated subjects compared with fosamprenavir alone (4/32 (13%) vs.16/29 (55%)).
In ART naive patients administered fosamprenavir without low dose ritonavir, the following amprenavir resistance associated mutations have been found either alone or in combination: I54L/M, V32I+I47V and M46I.

Resistance in vivo: protease inhibitor experienced subjects.

Many in vitro PI resistant variants and 322 of 433 (74%) clinical PI resistant variants with multiple protease inhibitor resistance mutations were susceptible to amprenavir. The principal protease mutation associated with cross resistance to amprenavir following treatment failure with other protease inhibitors was I84V, particularly when mutations L10I/V/F were also present. See Table 9.
The virologic response based upon baseline phenotype was assessed. Baseline isolates from PI experienced patients responding to fosamprenavir/ritonavir twice daily had a median shift in susceptibility to amprenavir relative to a standard wild type reference strain of 0.7 (range: 0.1 to 5.4, n = 62), and baseline isolates from individuals failing therapy had a median shift in susceptibility of 1.9 (range: 0.2 to 14, n = 29). Because this was a select patient population, these data do not constitute definitive clinical susceptibility breakpoints. Additional data are needed to determine clinically relevant breakpoints for Telzir.
Isolates from 15 of the 20 patients receiving twice daily fosamprenavir/ritonavir and experiencing virologic failure/ongoing replication were subjected to genotypic analysis. The following amprenavir resistance associated mutations were found either alone or in combination: V32I, M46I/L, I47V, I50V, I54L/M and I84V.
Fosamprenavir is not recommended for use as monotherapy, due to the rapid emergence of resistant virus.

Clinical trials.

Treatment naive patients.

Study APV30002 was a randomised, open label, two arm study to compare a regimen containing fosamprenavir 1400 mg + ritonavir 200 mg (N = 322) once daily to nelfinavir 1250 mg twice daily (N = 327), when administered in combination with abacavir 300 mg twice daily and 3TC 150 mg twice daily in HIV-1 infected treatment naive subjects over a 48 week period. The primary efficacy parameter for study APV30002 was the proportion of subjects with plasma HIV-1 RNA levels below 400 copies/mL at 48 weeks.
In the ITT population, the treatment groups were well matched with regard to demographic characteristics and baseline characteristics. See Table 10.
The median baseline CD4 count was low in both groups. A total of 55% of subjects had a CD4+ cell count < 200 cells/mm3 at baseline, and 20% of subjects had CD4+ cell counts < 50 cells/mm3. Overall, the baseline characteristics demonstrate that a more advanced treatment naive population was enrolled in this study compared to the population of previous studies in treatment naive subjects.
The proportion of subjects at week 48 with plasma HIV-1 RNA < 400 copies/mL and HIV-1 RNA < 50 copies/mL using the ITT (RD = F)* analysis are summarised in Table 11.
The results from study APV 30002 indicates that, in antiretroviral naive patients, fosamprenavir given once daily in combination with low dose ritonavir as part of a regimen including abacavir and lamivudine (given twice daily) showed comparable efficacy over 48 weeks compared to nelfinavir given twice daily in combination with abacavir/lamivudine.
Median HIV-1 RNA decreased from a baseline value of 4.78 log10 copies/mL in the fosamprenavir/ritonavir once daily group and 4.83 log10 copies/mL in the nelfinavir twice daily group to the lower limit of detection of assay (50 copies/mL or 1.69 log10 copies/mL) at week 20 in both groups and remained at this level through week 48.
Median changes from baseline in plasma HIV-1 RNA were comparable between treatment groups at each time point. The median change in plasma HIV-1 RNA from baseline to week 48 was -3.08 log10 copies/mL in the fosamprenavir/ritonavir once daily group and -2.96 log10 copies/mL in the nelfinavir twice daily group.
CD4+ cell counts increased in both treatment groups with median increases from baseline being similar in magnitude at week 48 (fosamprenavir/ritonavir: 203 cells mm3; nelfinavir twice daily: 207 cells mm3).

Treatment experienced patients.

Study APV30003 was a randomised, parallel group, three arm, open label, multicentre, comparative study of two dosage regimens of fosamprenavir 700 mg with ritonavir 100 mg twice daily (N = 105) and fosamprenavir 1400 mg and ritonavir 200 mg once daily (N = 105) versus lopinavir 400 mg and ritonavir 100 mg twice daily (N = 107), in HIV-1 infected subjects with previous PI experience, documented virological failure on a prior PI regimen, and currently receiving antiretroviral therapy. The primary endpoint was average area under the curve minus baseline plasma HIV-1 RNA.
In the ITT population, the treatment groups were largely comparable with regard to demographic and baseline characteristics, as indicated in Table 12.
Mean plasma HIV-1 RNA Average Area Under the Curve Minus Baseline (AAUCMB) values at week 48 are summarised in Table 13 for the ITT population observed analysis.
Table 14 provides plasma HIV-1 RNA at week 48 for < 400 and < 50 copies/mL using the ITT rebound or discontinued = failure (RD = F) analysis.
The fosamprenavir/ritonavir twice daily regimen and the lopinavir/ritonavir twice daily regimen showed similar immunological improvements through 48 weeks of treatment, as measured by median CD4+ cell count and change from baseline.
In PI experienced HIV infected subjects with evidence of virological failure, substantial virologic suppression was observed through 48 weeks of treatment with fosamprenavir 700 mg/ritonavir 100 mg twice daily or lopinavir 400 mg/ritonavir 100 mg twice daily dosing in combination with two RTIs. A lower level of virological suppression was observed through 48 weeks of treatment with fosamprenavir 1400 mg/ritonavir 200 mg once daily dosing in combination with two RTIs. After 48 weeks' treatment, the results of this study did not satisfy the criteria for noninferiority of either fosamprenavir/ritonavir once daily or fosamprenavir/ritonavir twice daily versus lopinavir/ritonavir twice daily with respect to the primary endpoint, plasma HIV-1 RNA AAUCMB.

Treatment naive patients dosed without ritonavir.

APV30001 was a randomised, open label study where treatment naive subjects were randomised to either receive fosamprenavir 1400 mg twice daily (N = 166) or nelfinavir 1250 mg twice daily (N = 83), when administered in combination with abacavir 300 mg twice daily and 3TC 150 mg twice daily. Most subjects were male and American Hispanic or black.
The median plasma HIV-1 RNA levels were 4.83 log10 copies/mL, and the median baseline CD4 cell count was 212 cells/mm3 at baseline. 20% of subjects had a prior history of a CDC class C event.
A greater proportion of subjects prematurely discontinued their randomised PI from the nelfinavir twice daily group (47%) than from the fosamprenavir twice daily (31%) group. More subjects in the nelfinavir twice daily group prematurely discontinued from randomised PI due to insufficient viral load response than in the fosamprenavir twice daily group.
Greater efficacy was obtained with fosamprenavir (66% of patients achieved HIV-1 RNA levels < 400 copies/mL) compared with nelfinavir (51% of patients) through 48 weeks of therapy. The proportions of patients with plasma HIV-1 RNA < 50 copies/mL at week 48 were also higher in the group treated with fosamprenavir (55% for Telzir compared with 41% for nelfinavir).

Children and adolescents.

The safety, pharmacokinetic profile, and virologic response of fosamprenavir have been evaluated in paediatric patients 2 to 18 years of age. Use of fosamprenavir in this patient population is supported by evidence from well controlled studies of fosamprenavir in adults with additional data from two open label studies of fosamprenavir in paediatric patients. Very limited data is available for paediatric patients less than 2 years of age.
In one study (APV29005), twice daily dosing regimen (Telzir with or without ritonavir) were evaluated in combination with other antiretroviral agents while in the second study (APV20003), once daily dosing regimen of Telzir with ritonavir were evaluated in combination with other antiretroviral agents. Doses and formulations (fosamprenavir tablets or oral suspension, ritonavir capsules or oral solution) were determined by patient weight and age.
APV29005 enrolled 25 patients aged 6 to 11 (the majority of whom were treated with fosamprenavir/ritonavir 18/3 mg/kg twice daily or the adult tablet regimen), and 29 patients aged 12 to 18 (the majority of whom were treated with the adult tablet regimen). Overall, 27 (50%) were PI naïve, 9 of whom were ART naïve, and 27 (50%) were PI experienced. Prior NRTI exposure was extensive, with median durations of 421 and 389 weeks for the PI naïve and experienced patients respectively. The median duration of prior PI exposure was 239 weeks. Overall, patients enrolled with a median 4.6 HIV-1 RNA log10 copies/mL (33% of whom had > 100,000 copies/mL at baseline) and a median % CD4+ cell of 18% (37% of whom had % CD4+ of < 15% at baseline).
Through 24 weeks of therapy, 70% (19/27) of protease inhibitor naïve and 56% (15/27) of protease inhibitor experienced patients achieved and maintained a plasma HIV-1 RNA < 400 copies/mL (ITT(E), TLOVR). In the ITT(E) population (observed analysis) at week 24 the median % CD4+ cell counts increased by 8% in the PI naïve subjects and 4% in the PI experienced subjects.
The once daily study APV20003 enrolled 52 patients aged 6-18. Of these, 26 (50%) were PI naïve and 26 (50%) were PI experienced. At week 24 of therapy, 62% (16/26) of protease inhibitor naïve and 42% (11/26) of protease inhibitor experienced patients achieved a plasma HIV-1 RNA < 400 copies/mL (ITT(E), TLOVR). At week 48 of therapy, 46% (12/26) of protease inhibitor naïve and 31% (8/26) of protease inhibitor experienced patients achieved HIV-1 RNA < 400 copies/mL.
There are currently insufficient data on pharmacokinetics, safety and antiviral response of fosamprenavir with ritonavir in children below 6 years of age.
No direct comparative studies have been undertaken in children or adolescents.

5.2 Pharmacokinetic Properties

After oral administration, fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate prior to systemic circulation. The conversion of fosamprenavir to amprenavir appears to primarily occur in the gut epithelium.
Amprenavir metabolism is inhibited by ritonavir, via inhibition of CYP3A4, resulting in increased plasma concentrations of amprenavir.
The pharmacokinetic properties of amprenavir following co-administration of fosamprenavir and ritonavir have been evaluated in healthy adult subjects and HIV infected patients and no substantial differences were observed between these two groups.

Absorption.

After multiple dose oral administration of fosamprenavir 1400 mg once daily and ritonavir 200 mg once daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady-state peak plasma amprenavir concentration (Cmax) of 7.24 (6.32-8.28) microgram/mL occurring approximately 2 (0.8-5.0) hours after dosing (Tmax). The geometric mean steady-state plasma amprenavir trough concentration (Cmin) was 1.45 (1.16-1.81) microgram/mL and AUC24,ss was 69.4 (59.7-80.8) h.microgram/mL.
After multiple dose oral administration of fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily, amprenavir was rapidly absorbed with a geometric mean (95% CI) steady-state peak plasma amprenavir concentration (Cmax) of 6.08 (5.38-6.86) microgram/mL occurring approximately 1.5 (0.75-5.0) hours after dosing (Tmax). The geometric mean steady-state plasma amprenavir trough concentration (Cmin) was 2.12 (1.77-2.54) microgram/mL and AUC24,ss was 79.2 (69.0-90.6) h.microgram/mL.
The absolute bioavailability of fosamprenavir in humans has not been established. See Figure 1.
Administration of the fosamprenavir oral tablet formulation (1400 mg) with a high fat meal did not alter plasma amprenavir pharmacokinetics as compared to the administration of this formulation in the fasted state. Fosamprenavir tablets may be taken without regard to food intake.

Distribution.

The apparent volume of distribution is decreased by approximately 40% when fosamprenavir is co-administered with ritonavir, most likely due to an increase in amprenavir bioavailability.
The apparent volume of distribution of amprenavir following administration of fosamprenavir is approximately 430 litres (6 L/kg assuming a 70 kg bodyweight), suggesting a large volume of distribution, with penetration of amprenavir freely into tissues beyond the systemic circulation. The concentration of amprenavir in cerebrospinal fluid is less than 1% of the plasma concentration.
Amprenavir is approximately 90% protein bound. It is bound to the alpha1-acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.

Metabolism.

Following oral administration, fosamprenavir is rapidly and almost completely hydrolysed to amprenavir and inorganic phosphate as it is absorbed through the gut epithelium. Amprenavir is primarily metabolised by the liver with less than 1% excreted unchanged in the urine. The primary route of metabolism is via the cytochrome P450 3A4 enzyme. Amprenavir metabolism is inhibited by ritonavir, via inhibition of CYP3A4, resulting in increased plasma concentrations of amprenavir. Amprenavir is a less potent inhibitor of CYP3A4. Therefore drugs that are inducers, inhibitors or substrates of CYP3A4 must be used with caution when administered concurrently with fosamprenavir and ritonavir (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

Following administration of fosamprenavir, the half-life of amprenavir is 7.7 hours. The plasma amprenavir half-life is increased when fosamprenavir is co-administered with ritonavir. The primary route of elimination of amprenavir is via hepatic metabolism with less than 1% excreted unchanged in the urine. The metabolites account for approximately 14% of the administered amprenavir dose in the urine, and approximately 75% in the faeces.

Special populations.

Paediatrics.

The pharmacokinetics of amprenavir in children (2 years of age and above) and adolescents are similar to those in adults. Dosages of fosamprenavir (oral suspension or tablets) plus ritonavir (oral solution or capsules) were administered to subjects. The dosage regimen studies were on an age/weight basis. Mean steady-state amprenavir pharmacokinetic parameters in this population are presented by dosing regimen and age group in Table 15.
Currently there are insufficient pharmacokinetic data in children < 2 years of age to support dosing in this age group.

Elderly.

The pharmacokinetics of fosamprenavir when given in combination with ritonavir has not been studied in patients over 65 years of age. When treating elderly patients, consideration should be given to potential hepatic, renal or cardiac dysfunction, concomitant disease or other drug therapy.

Impaired renal function.

Patients with renal impairment have not been specifically studied. Renal elimination is not a major route of elimination of amprenavir or ritonavir. The impact of renal impairment on amprenavir and ritonavir elimination should be minimal, therefore no dose adjustment of the fosamprenavir/ritonavir combination is considered necessary.

Impaired hepatic function.

Fosamprenavir is converted in man to amprenavir. The principal route of amprenavir and ritonavir elimination is hepatic metabolism. The plasma amprenavir pharmacokinetics were evaluated in a repeat dose study in HIV-1 infected adult subjects with hepatic impairment receiving fosamprenavir with ritonavir compared to matched control subjects with normal hepatic function.
For subjects with mild hepatic impairment (Child-Pugh (C-P) score of 5-6), a dosage regimen of fosamprenavir 700 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is recommended (see Section 4.2 Dose and Method of Administration) based on slightly higher plasma amprenavir Cmax (17%), slightly higher plasma amprenavir AUC(0-T) (22%), and similar CT values compared to subjects with normal hepatic function receiving the standard fosamprenavir/ritonavir 700 mg/100 mg twice daily regimen.
For subjects with moderate hepatic impairment (C-P score of 7-9), a dosage regimen of fosamprenavir 450 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily is recommended (see Section 4.2 Dose and Method of Administration). Although the fosamprenavir 450 mg twice daily + ritonavir 100 mg once daily dosage regimen is predicted to deliver approximately 35% lower plasma total amprenavir CT values, plasma unbound amprenavir CT values will be approximately 67% higher than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg/100 mg twice daily regimen.
For subjects with moderate hepatic impairment, the fosamprenavir 700 mg once daily + ritonavir 100 mg once daily regimen delivered 24% lower plasma amprenavir Cavg, 65% lower CT, and approximately 42% lower unbound CT compared to subjects with normal hepatic function receiving the standard fosamprenavir/ritonavir 700 mg/100 mg twice daily regimen. Therefore, a fosamprenavir tablet regimen in subjects with moderate hepatic impairment could not achieve comparable plasma amprenavir pharmacokinetics to the fosamprenavir/ritonavir 700 mg/100 mg twice daily regimen in subjects with normal hepatic function.
In subjects with severe hepatic impairment (C-P score of 10-13), a reduced dose of fosamprenavir 300 mg twice daily with a reduced dosing frequency of ritonavir 100 mg once daily delivered 19% lower plasma amprenavir Cmax, 23% lower AUC(0-T), and 38% lower CT values, but similar unbound plasma amprenavir CT values than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg/100 mg twice daily regimen. Despite reducing the dosing frequency of ritonavir, subjects with severe hepatic impairment had 64% higher ritonavir Cmax, 40% higher ritonavir Cavg, and 38% higher ritonavir CT than achieved in subjects with normal hepatic function receiving the standard fosamprenavir with ritonavir 700 mg/100 mg twice daily regimen.

Pregnancy.

Amprenavir pharmacokinetic parameters were assessed in 10 HIV-infected pregnant women receiving fosamprenavir/ritonavir 700/100 mg twice daily. Six participants contributed second trimester data and nine contributed to both the third-trimester and postpartum analysis.
Geometric mean amprenavir exposure was lower in the second and third trimester than postpartum. Second trimester vs. postpartum APV geometric mean ratios (90% CI) were: AUC(0 - 12): 0.65 (0.47, 0.89), Cmax 0.63 (0.47, 0.85), C12: 0.64 (0.45, 0.93). Third trimester vs. postpartum geometric mean ratios (90% CI) were AUC(0 - 12) 0.75 (0.57, 1.00), Cmax 0.81 (0.62, 1.06) C12 0.62 (0.48, 0.92). Geometric mean (95% CI) C12 values were 1.31 (0.97, 1.77), 1.34 (0.95, 1.89), and 2.03 (1.46, 2.83) micrograms/mL for the second trimester, third trimester, and postpartum, respectively and within the range of values in non-pregnant patients. Geometric mean C12 levels for all pregnancy phases were 9-15-fold above the mean APV protein-adjusted IC50 of 0.146 microgram/mL for wild-type HIV strains.
Seven infant cord blood samples were analysed and placental transfer of amprenavir has been observed. The mean (SD) umbilical cord amprenavir blood concentration was 0.11 (0.07) microgam/mL. The maternal plasma concentration at delivery was 0.43 (0.29) microgram/mL. The ratio (95% CI) of cord to maternal peripheral plasma concentration was 0.267 (0.241, 0.297).

5.3 Preclinical Safety Data

Genotoxicity.

Fosamprenavir was not mutagenic or genotoxic in a battery of in vitro and in vivo assays. These assays included bacterial reverse mutation (Ames), mouse lymphoma, rat micronucleus, and chromosome aberrations in human lymphocytes.

Carcinogenicity.

In long-term carcinogenicity studies, fosamprenavir was administered orally for up to 104 weeks at doses of 250, 400, or 600 mg/kg/day in mice and at doses of 300, 825, or 2250 mg/kg/day in rats. Exposures to amprenavir at these doses were 0.2 to 0.3-fold (mice) and 0.3 to 0.7-fold (rats) those in humans given 1400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily. Exposures in the carcinogenicity studies were 0.1 to 0.3-fold (mice) and 0.3 to 0.6-fold (rats) those in humans given 700 mg of fosamprenavir plus 100 mg ritonavir twice daily. There was an increase in hepatocellular adenomas and hepatocellular carcinomas at all doses in male mice, and in hepatocellular adenomas and thyroid follicular cell adenomas at all doses in male rats and at 825 and 2250 mg/kg/day in female rats. The relevance of the hepatocellular findings in the rodents for humans is uncertain. Repeat dose studies with fosamprenavir in rats produced effects consistent with enzyme induction, which predisposes rats, but not humans, to thyroid neoplasms. In addition, in rats only there was an increase in interstitial cell hyperplasia at 825 and 2250 mg/kg/day, and an increase in uterine endometrial adenocarcinoma at 2250 mg/kg/day. The incidence of endometrial findings was slightly increased over concurrent controls, but within background range for female rats. The relevance of the uterine endometrial adenocarcinoma findings in rats for humans is uncertain. The carcinogenicity of fosamprenavir in combination with ritonavir has not been tested in animals.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Microcrystalline cellulose, croscarmellose sodium, povidone K30, magnesium stearate, colloidal silicon dioxide.

Tablet coating.

Hypromellose, titanium dioxide (E171), glycerol triacetate, iron oxide red (E172).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Telzir film-coated tablets are supplied in High-Density Polyethylene (HDPE) bottles containing 60 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Fosamprenavir calcium has a solubility approximately 0.31 mg/mL in water at 25°C.
The chemical name of fosamprenavir is (3S)-tetrahydrofuran-3-yl (1S,2R)-3-[[(4-aminophenyl) sulphonyl](isobutyl) amino]-1-benzyl-2-(phosphonooxy) propylcarbamate monocalcium. Fosamprenavir is a single stereoisomer with the (3S)(1S,2R) configuration.
It has a molecular formula of C25H34CaN3O9PS and a molecular weight of 623.7.

Chemical structure.


CAS number.

226700-81-8.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes